Hibernating mammals actively lower their body temperature to reduce energy expenditure when facing food scarcity¹. This ability to induce a hypometabolic state has evoked great interest owing to its potential medical benefits^2,3. Here we show that a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation. In this state, although body temperature and levels of oxygen consumption are kept very low, the ability to regulate metabolism still remains functional, as in hibernation⁴. There was no obvious damage to tissues and organs or abnormalities in behaviour after recovery from this state. Our findings could enable the development of a method to induce a hibernation-like state, which would have potential applications in non-hibernating mammalian species including humans.

Significance: Narcolepsy-cataplexy is a debilitating disorder characterized by excessive daytime sleepiness (sleep attacks) and cataplexy, a sudden bilateral loss of muscle tone often triggered by emotion. The disease is caused by a selective loss of hypothalamic neurons producing the neuropeptide orexin. Currently, only symptomatic therapies are available for narcolepsy. Here, we examine the pharmacological effect of YNT-185, a nonpeptide, selective agonist for the orexin type-2 receptor in mouse models of narcolepsy-cataplexy. We show that peripheral administration of YNT-185 significantly ameliorates the narcolepsy symptoms in model mice, providing a proof-of-concept for the mechanistic treatment of narcolepsy with orexin receptor agonists. YNT-185 also promotes wakefulness in wild-type mice, suggesting that orexin receptor agonists may be useful for treating sleepiness due to other causes.

Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor ⁺ (p75NTR ⁺ ) fibroblasts and homeostatic chemokine–producing fibroblasts inside TLTs, and retinoic acid–producing fibroblasts around TLTs. Deletion of CD4 ⁺ cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.

Dysbiosis of the gut microbiota affects physiological processes, including brain functions, by altering the intestinal metabolism. Here we examined the effects of the gut microbiota on sleep/wake regulation. C57BL/6 male mice were treated with broad-spectrum antibiotics for 4 weeks to deplete their gut microbiota. Metabolome profiling of cecal contents in antibiotic-induced microbiota-depleted (AIMD) and control mice showed significant variations in the metabolism of amino acids and vitamins related to neurotransmission, including depletion of serotonin and vitamin B6, in the AIMD mice. Sleep analysis based on electroencephalogram and electromyogram recordings revealed that AIMD mice spent significantly less time in non-rapid eye movement sleep (NREMS) during the light phase while spending more time in NREMS and rapid eye movement sleep (REMS) during the dark phase. The number of REMS episodes seen in AIMD mice increased during both light and dark phases, and this was accompanied by frequent transitions from NREMS to REMS. In addition, the theta power density during REMS was lower in AIMD mice during the light phase compared with that in the controls. Consequently, the gut microbiota is suggested to affect the sleep/wake architecture by altering the intestinal balance of neurotransmitters.